Thayer W P, Kraft J R, Tompkins S M, Moore J C, Jensen P E
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
J Immunol. 1999 Sep 1;163(5):2549-54.
The immune response to insulin is regulated by MHC class II genes. Immune response (Ir) gene-linked low responsiveness to protein Ags can be mediated by the low affinity of potential antigenic determinants for MHC molecules (determinant selection) or by the influence of MHC on the functional T cell repertoire. Strong evidence exists that determinant selection plays a key role in epitope immunodominance and Ir gene-linked unresponsiveness. However, the actual measurement of relative MHC-binding affinities of all potential peptides derived from well-characterized model Ags under Ir gene regulation has been very limited. We chose to take advantage of the simplicity of the structure of insulin to study the mechanism of Ir gene control in H-2b mice, which respond to beef insulin (BINS) but not pork insulin (PINS). Peptides from these proteins, including the immunodominant A(1-14) determinant, were observed to have similar affinities for purified IAb in binding experiments. Functional and biochemical experiments suggested that PINS and BINS are processed with similar efficiency. The T cell response to synthetic pork A(1-14) was considerably weaker than the response to the BINS peptide. We conclude that the poor immunogenicity of PINS in H-2b mice is a consequence of the T cell repertoire rather than differences in processing and presentation.
对胰岛素的免疫反应受MHC II类基因调控。免疫反应（Ir）基因连锁的对蛋白质抗原的低反应性可由潜在抗原决定簇与MHC分子的低亲和力（决定簇选择）介导，或由MHC对功能性T细胞库的影响介导。有强有力的证据表明，决定簇选择在表位免疫显性和Ir基因连锁的无反应性中起关键作用。然而，在Ir基因调控下，对来自特征明确的模型抗原的所有潜在肽段的相对MHC结合亲和力的实际测量非常有限。我们选择利用胰岛素结构的简单性来研究H-2b小鼠中Ir基因控制的机制，H-2b小鼠对牛胰岛素（BINS）有反应，但对猪胰岛素（PINS）无反应。在结合实验中，观察到来自这些蛋白质的肽段，包括免疫显性的A(1-14)决定簇，对纯化的IAb具有相似的亲和力。功能和生化实验表明，PINS和BINS的加工效率相似。T细胞对合成猪A(1-14)的反应明显弱于对BINS肽段的反应。我们得出结论，PINS在H-2b小鼠中免疫原性差是T细胞库的结果，而不是加工和呈递方面的差异。
